Asymmetric induction in 8π electrocyclizations. Design of a removable chiral auxiliary

Article abstract of DOI:10.1021/ol202932x

The pseudo C₂ symmetric trans diphenyl oxazoline group acts as an effective chiral auxiliary in the 8π, 6π tandem electrocyclization of a substituted tetraene 1-carboxylic acid. Assignment of absolute stereochemistry to the [4.2.0] bicyclooctad

Full text of DOI:10.1021/ol202932x

ORGANIC
LETTERS
2012
Vol. 14, No. 1
138–141
Asymmetric Induction in 8π
Electrocyclizations. Design of a
Removable Chiral Auxiliary
Keunsoo Kim, Joseph W. Lauher, and Kathlyn A. Parker*
Department of Chemistry, Stony Brook University, Stony Brook, New York 11733,
United States
kparker@notes.cc.sunysb.edu
Received October 30, 2011
ABSTRACT
The pseudo C2 symmetric trans diphenyl oxazoline group acts as an effective chiral auxiliary in the 8π, 6π tandem electrocyclization of a
substituted tetraene 1-carboxylic acid. Assignment of absolute stereochemistry to the [4.2.0] bicyclooctadiene product supports a model in which
both s-cis and s-trans conformations favor the transition states with the same helical twist. This assignment prefaces the development of analogs
of SNF4435 C and D. These natural products demonstrate activity as androgen receptor antagonists and as multidrug resistance (mdr) reversal
agents.
1,3,5,7-Octatetraenes in which the two internal olefins
have the Z-configuration are thermally unstable with
respect to the 8π, 6π electrocyclization cascade. Thus,
their preparation leads directly to compounds that con-
tain the [4.2.0] bicyclooctadiene ring system.
has moved center stage because the bicyclooctadiene is
a key structural component of a number of interesting
natural products. In fact, the 8π, 6π electrocyclization
This chemistry was studied in the 1960s, most notably
by Marvel and by Huisgen, who demonstrated in simple
substituted systems (Scheme 1) that it followed the newly
revealed WoodwardꢀHoffmann rules.1 More recently, it
Scheme 1. Prototypical 8π, 6π Tandem Cyclizations
(1) (a) Marvell, E. N.; Seubert, J. J. Am. Chem. Soc. 1967, 89, 3377.
(b) Marvell, E. N.; Caple, G.; Schatz, B. Tetrahedron Lett. 1965, 385.
(c) Huisgen, R.; Dahmen, A.; Huber, H. J. Am. Chem. Soc. 1967, 89,
7130. (d) Huisgen, R.; Dahmen, A.; Huber, H. Tetrahedron Lett. 1969,
1461. See also:(e) Vogel, E.; Grimme, W.; Dinne, E. Tetrahedron Lett.
1965, 391.
r
10.1021/ol202932x
Published on Web 12/06/2011
2011 American Chemical Society

sequence is thought to be one of the transformations in
the biosynthetic schemes leading to these compounds
and it has served as the conceptual basis of the chemical
synthesis of the endiandric acids,2 SNF4435 C and D
(4 and 5, Figure 1),3 elysiapyrones A and B,4 ocellapyrones
A and B,5 shimalactones A and B,6 and “pre-kingianin A,”
the presumed biosynthetic precursor of kingianin A.7
have tested candidate auxiliaries in the 9-(p-nitrophenyl)-
4,6,8-trimethyl-2,4,6,8-tetraenoic acid (8, R* = CO2H)
system (Scheme 2).
Scheme 2. Synthesis of the [4.2.0] Bicyclo System of SNF
Analogs
Figure 1. SNF4435 C and SNF4435 D.
Although the well-defined relative stereochemistry that
results from the thermal 8π, 6π cascade has been under-
stood for more than 40 years, the possibility of asymmet-
ric induction in this conversion by means of a removable
auxiliary was not investigated until recently. In a test of
this refinement, we prepared a series of chiral auxiliary-
bearing tetraene carboxylic acid esters and observed the
ratios of diastereomeric 8π, 6π products.8 Although none
of the substrates gave a large excess of one of the dia-
stereomers, our work in the series provided context for
further experiments.
High asymmetric induction in electrocyclizations is an
intellectual challenge and a practical problem.9 Herein, we
describe the rational design and effective use of oxazoline
auxiliaries that impose a significant bias for one of the two
helical arrangements that lead to 8π electrocyclization.
Because of our particular interest in the preparation of
medicinally active analogs of the SNF compounds, we
(2) Nicolaou, K. C.; Petasis, N. A.; Uenishi, J.; Zipkin, R. E. J. Am.
Chem. Soc. 1982, 104, 5557.
(3) (a) Parker, K. A.; Lim, Y.-H. J. Am. Chem. Soc. 2004, 126, 15968.
(b) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E. Org.
Lett. 2005, 7, 2473. (c) Beaudry, C. M.; Trauner, D. Org. Lett. 2005, 7,
4475. See also:(d) Kawamura, T.; Fujimaki, T.; Hamanaka, N.; Torii,
K.; Kobayashi, H.; Takahashi, Y.; Igarashi, M.; Kinoshita, N.; Nishimura,
Y.; Tashiro, E.; Imoto, M. J. Antibiot. 2010, 63, 601.
This tetraene system, prepared by coupling the stan-
nane 63c with an iododiene 7, offers the advantage of
providing exclusively the endo products 11a/12a10 in the
second electrocyclic step (i.e., the 6π electrocyclization).
Consequently, in this system, analysis of the asymmetric
induction is simpler than in cases in which both endo and
exo products are formed.
(4) Barbarow, J. E.; Miller, A. K.; Trauner, D. Org. Lett. 2005
7, 2901.
(5) Miller, A. K.; Trauner, D. Angew. Chem., Int. Ed. 2005, 44, 4602.
(6) (a) Sofiyev, V.; Navarro, G.; Trauner, D. Org. Lett. 2008, 10, 149.
(b) Wei, H.; Itoh, T.; Kinoshita, M.; Kotoku, N.; Aoki, S.; Kobayashi,
M. Tetrahedron 2005, 6, 8054. (c) Wei, H.; Itoh, T.; Kotoku, N.;
Kobayashi, M. Heterocycles 2006, 68, 111.
(7) Sharma, P.; Ritson, D. J.; Burnley, J.; Moses, J. E. Chem. Commun.
2011, 47, 10605.
(8) (a) Parker, K. A.; Wang, Z. Org. Lett. 2006, 8, 3553. (b) For
examples of modest levels of chiral induction in a related sequence, the
8π electrocyclization/transannular aldol cascade, see: Paquette, L. A.;
Tae, J. J. Org. Chem. 1998, 63, 2022.
(9) Thompson, S.; Coyne, A. G.; Knipe, P. C.; Smith, M. D. Chem.
Soc. Rev. 2011, 40, 4217.
(10) Although the ratio of diastereomers was evident from the NMR
spectrum of the product mixture in each case, the relative stereochem-
istry between the bicyclooctadiene and the chiral auxiliary for the two
diastereomers was assigned only for the product pairs 11a/12a (from
crystallography) and 11f/12f (by comparison with 11a and 12a).
Org. Lett., Vol. 14, No. 1, 2012
139

carbonyl oxygen of the parent carboxylic acid. Further-
more, rational design would become more feasible if
we could reduce the number of possible transition state
candidates from a minimum of four (as is the case for
esters and amides) to two (as would be the case if R* were
a C2 symmetric or pseudo C2 symmetric functional group).
Consequently, we considered the effect of a trans-4,
5-disubstituted oxazoline, a moiety that has a pseudo
C2 axis (Figure 2), on the helical transition state confor-
mations available for 8π closure.
Table 1. Preparation of Diastereomers 11 þ 12
Figure 2. Four possible helical transition states.
Focusing now on the interactions between the nitro-
phenyl group (Ar) and the oxazoline substituents (Ar0) in
the helical transition states A, A0, B, and B0, we found a
convincing steric preference for the A, A0 pair. This model
predicts that the major product from the coupling/8π, 6π
cascade is bicyclooctadiene 12f rather than its diastereo-
mer 11f.
The diphenyl oxazoline substrate 7f was prepared in
seven steps from commercially available materials (see
Supporting Information) and subjected to the coupling
cascade (Scheme 2). A 6:1 ratio of two diastereomers
rewarded the rational design effort.11
Reasoning that an additional substituent on the ox-
azoline would, to a first approximation, leave the helicity
preference unaltered, we examined substrate 7g, derived
from the inexpensive (S)-(ꢀ)-2-amino-3-methyl-1,1-
diphenylbutan-1-ol. The presence of the additional sub-
stituent on the oxazoline ring should disfavor the transi-
tion state corresponding to A but not disfavor any of the
other transition states. In the event, the substrate pre-
pared to test this premise (entry g) provided a modest
preference for one diastereomer.
Initial experiments with substrates in which the carbon-
yl group was functionalized as an amide derived from
readily accessible phenylglycinol (entries a and b in
Table 1; see Supporting Information for synthesis of
substrates) were unimpressive; the diastereomeric ratio
(dr) in the product mixture hovered around 1:1. It is prob-
able that the s-cis,syn and s-trans,syn transition states for
closure of these primary amide substrates, like those of the
ester substrates,8a are nearly isoenergetic.
Thinking that we might favor one helicity over the
other by introducing a second substituent on the nitrogen,
we tested the secondary amide system (entry c); again
there was no preference for either diastereomer. Similarly,
the substrate that contained the bis[(S)-1-phenethyl]-
amine auxiliary (entry d) provided almost equal amounts
of two diastereomeric products.
Next, we reasoned that introduction of dipole interac-
tions would favor one of the four possible transition states
over the others and we examined the acyl oxazolidinone
system (entry e). Again the ring closure proved to be
stereorandom.
Confirmation of our model for chiral induction in 8π
electrocyclizations required correlation of one of the pro-
ducts with material of known absolute stereochemistry.
We therefore returned to our analysis of the transition
states for the 8π closure of the tetraene esters.8a We re-
cognized that a cyclic chiral auxiliary would be more
effective if the ring included the carbonyl carbon and the
(11) In the terminology for the SNF compounds introduced by us,
the endo product is the isomer in which the aryl substituent is cis to
the cyclohexadiene ring; see: Parker, K. A.; Lim, Y. -H. Org. Lett. 2004,
6, 161.
140
Org. Lett., Vol. 14, No. 1, 2012

For this purpose, we exploited the crystallinity of one of
the isomers of 11a/12a. These two compounds are easily
separable on silica gel chromatography with 1:1 EtOAc/
hex.12 The slower moving isomer was recrystallized from
CHCl3/hex. Then slow evaporation of a solution in
MeOH/Et2O gave needles that were suitable for X-ray
analysis. The relative stereochemistry of the slower moving
isomer, determined by the crystallographic experiment, is
as shown in Figure 3; this corresponds to isomer 11a.
with that of authentic 12a. In this way, we were able to
assign the stereochemistry of the major electrocyclization
product from substrate 7f as oxazoline 12f.
Scheme 3. Relationship of Major Product from 7f with more
Rapidly Moving Stereoisomer from the 11a/12a Pair
To our knowledge, the coupling/8π, 6π electrocycliza-
tion cascade of substrate 7f is the first example of the
exploitation of the pseudo C-2 axis of trans-4,5-disubsti-
tuted oxazolines for asymmetric induction. The under-
lying design principle allows a simple analysis of the
energies of the transition states that lead to diastereo-
meric products. We anticipate the use of these oxazoline
auxiliaries for providing asymmetric induction in other
reactions of unsaturated carboxylic acid systems. Enan-
tiomeric carboxylic acids 11 (R = CO2H) and 12 (R =
CO2H) are key intermediates for elaboration to stereo-
chemically homogeneous analogs of SNF4435 C and D.
Figure 3. X-ray crystal structure of 11a.
It remained for us to determine whether the chirality of
the bicyclooctadiene moiety of our major product from
substrate 7f corresponds to that of amide 11a or to amide
12a. For this purpose, we converted the major product
from oxazoline 7f to the corresponding (S)-(þ)-2-phenyl-
glycinol amide. This was accomplished in three steps
(Scheme 3; see the Supporting Information for details).
The tlc behavior of the (S)-(þ)-2-phenylglycinol amide
derived from the major component of the mixture from 7f
was inconsistent with that of authentic 11a and consistent
Acknowledgment. This work was supported by the
National Institutes of Health (GM 74776) and the
National Science Foundation (CHE-0131146, NMR in-
strumentation and CHE-0840483, diffractometer).
Supporting Information Available. Schemes for the
synthesis of substrates 7aꢀg and authentic 11f/12f, ex-
perimental procedures with analytical data for all new
compounds, and crystallographic cif file for structure
11a. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) An authentic 1:1 mixture of oxazolines 11f and 12f was prepared
in three steps from racemic carboxylic acid 11/12 (R = CO2H) and
(S),(S)-diphenylglycinol. For the scheme and experimental details, see
the Supporting Information.
(13) A large separation factor for another pair of diastereomeric
phenylglycinol amides was noted by Baek, D. J.; Daniels, S. B.; Reed,
P. E.; Katzenellenbogen, J. A. J. Org. Chem. 1989, 54, 3962.
Org. Lett., Vol. 14, No. 1, 2012
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